Muscle is the largest organ system of the body, comprising approximately 30% of body mass. Muscle is considered one of the most adaptable tissues, responding quickly to use and disuse, and is capable of regeneration, hypertrophy, and alteration of metabolic status over relatively short periods of time. Muscle dysfunction is an important human health problem. Inherited disorders of muscle, composed primary of muscular dystrophies of the most common and most devastating inborn errors of human metabolism. Weakness due to aging (sarcopenia), and during space travel are also major concerns regarding the loss of muscle function. There are clearly many advantages of muscle as an organ system in which to test the ability of exogenously added genes to modulate cellular function. However, as the muscle gene delivery field as expanded and matured over the last few years, significant hurdles facing practical applications have become recognized. It is these remaining hurdles that are the focus of this program project. In this program project, we combine the complementary expertise of a group of seven independent investigators who have a track-record of synergistic collaboration, and commitment to the field of muscle, muscle disease, and muscle gene delivery. The interdependency of the different projects and sponsoring laboratories is evident through the extensive collaborative preliminary data that is presented, a long history of co- authored publications, and established shared training grants, group meetings, and journal clubs. Research projects are as follows: Project 1 (Dr. Xiao), adeno-associated virus (AAV) vectors to improve mature muscle function by gene delivery. Project 2 (Dr. Clemens), Long-term rescue of muscle function by dystrophin delivery using novel adenoviral vectors. Project 3 (Dr. Huard), Definition and circumvention of maturation-dependent infectivity of muscle by adenovirus. Project 4 (Dr. Hoffman), Development of targeting ligands for systemic delivery to muscle. Three Cores support the research projects; Administrative Core (Dr. Hoffman), Muscle Physiology Core (Dr. Watchko), and Mouse Breeding Core (Dr. Clemens).